The chemical synthesis and biological evaluation of novel, highly potent agents for the treatment of both severe acute and chronic pain associated with cancer and other diseases that has minimal side effects such as addiction liability, imniunosuppression and respiratory depression is very urgent. For "proof of principle," in Phase I, congeners of agents 100-fold more active than morphine will be synthesized and tested in vitro and in vivo for analgesic activity and safety. In later studies, additional lead optimization of the most promising drug candidate will be explored by parallel synthesis combinatorial chemistry. In Phase II, the optimized compounds will be tested in animals for analgesic activity and thorough safety evaluation. Because there is a great need for stable, long lasting, potent, orally active pain medication to treat pain associated with cancer and other diseases, the successful completion of the work proposed will lead to important new innovation in the pain medication field. The long-term goal of our work is to develop effective anti-pain agents in animals that can be taken forward into the clinic for testing as a human medication. We expect that development of the novel pain relief drug candidates proposed will provide new agents useful in the amelioration of human suffering. This will improve the quality of life for tens of thousands of Americans. PROPOSED COMMERCIAL APPLICATION: The need for potent, orally active pain medication to alleviate the severe pain experienced by patients with cancer and other diseases is immense. Procurement of a long lasting oral anti-pain medication that has significantly fewer side effects than narcotics currently in use will provide a therapeutic that is currently not available. The potential commercial application of the work is that the research could lead to a 'blockbuster' drug product.